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Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51
Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257675/ https://www.ncbi.nlm.nih.gov/pubmed/33531658 http://dx.doi.org/10.1038/s41418-020-00733-4 |
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author | Manic, Gwenola Musella, Martina Corradi, Francesca Sistigu, Antonella Vitale, Sara Soliman Abdel Rehim, Sara Mattiello, Luca Malacaria, Eva Galassi, Claudia Signore, Michele Pallocca, Matteo Scalera, Stefano Goeman, Frauke De Nicola, Francesca Guarracino, Andrea Pennisi, Rosa Antonangeli, Fabrizio Sperati, Francesca Baiocchi, Marta Biffoni, Mauro Fanciulli, Maurizio Maugeri-Saccà, Marcello Franchitto, Annapaola Pichierri, Pietro De Maria, Ruggero Vitale, Ilio |
author_facet | Manic, Gwenola Musella, Martina Corradi, Francesca Sistigu, Antonella Vitale, Sara Soliman Abdel Rehim, Sara Mattiello, Luca Malacaria, Eva Galassi, Claudia Signore, Michele Pallocca, Matteo Scalera, Stefano Goeman, Frauke De Nicola, Francesca Guarracino, Andrea Pennisi, Rosa Antonangeli, Fabrizio Sperati, Francesca Baiocchi, Marta Biffoni, Mauro Fanciulli, Maurizio Maugeri-Saccà, Marcello Franchitto, Annapaola Pichierri, Pietro De Maria, Ruggero Vitale, Ilio |
author_sort | Manic, Gwenola |
collection | PubMed |
description | Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations. |
format | Online Article Text |
id | pubmed-8257675 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82576752021-07-23 Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 Manic, Gwenola Musella, Martina Corradi, Francesca Sistigu, Antonella Vitale, Sara Soliman Abdel Rehim, Sara Mattiello, Luca Malacaria, Eva Galassi, Claudia Signore, Michele Pallocca, Matteo Scalera, Stefano Goeman, Frauke De Nicola, Francesca Guarracino, Andrea Pennisi, Rosa Antonangeli, Fabrizio Sperati, Francesca Baiocchi, Marta Biffoni, Mauro Fanciulli, Maurizio Maugeri-Saccà, Marcello Franchitto, Annapaola Pichierri, Pietro De Maria, Ruggero Vitale, Ilio Cell Death Differ Article Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations. Nature Publishing Group UK 2021-02-02 2021-07 /pmc/articles/PMC8257675/ /pubmed/33531658 http://dx.doi.org/10.1038/s41418-020-00733-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Manic, Gwenola Musella, Martina Corradi, Francesca Sistigu, Antonella Vitale, Sara Soliman Abdel Rehim, Sara Mattiello, Luca Malacaria, Eva Galassi, Claudia Signore, Michele Pallocca, Matteo Scalera, Stefano Goeman, Frauke De Nicola, Francesca Guarracino, Andrea Pennisi, Rosa Antonangeli, Fabrizio Sperati, Francesca Baiocchi, Marta Biffoni, Mauro Fanciulli, Maurizio Maugeri-Saccà, Marcello Franchitto, Annapaola Pichierri, Pietro De Maria, Ruggero Vitale, Ilio Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 |
title | Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 |
title_full | Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 |
title_fullStr | Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 |
title_full_unstemmed | Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 |
title_short | Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 |
title_sort | control of replication stress and mitosis in colorectal cancer stem cells through the interplay of parp1, mre11 and rad51 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257675/ https://www.ncbi.nlm.nih.gov/pubmed/33531658 http://dx.doi.org/10.1038/s41418-020-00733-4 |
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